Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
  • C07D213/32—Sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
  • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to new thioformamide derivatives of general formula:
• R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain
• Het represents a heterocyclic radical of aromatic character containing one or two nitrogen atoms such as pyridyle-3, pyridyle-4, pyridazinyl-3, pyrazinyl or quinolyle-3
• X represents a sulfur or oxygen atom
• Y represents a sulfur or oxygen atom, a valence bond or a methylene radical.
• the products of general formula (!) In which the symbols R, Het, X and Y are defined as above can be prepared by the action of an amine of general formula: in which R is defined as above on a dithioester of general formula: in which the symbols Het, X and Y are defined as above and R 'represents an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain or a benzyl or carboxymethyl radical.
• amine of general formula (II) without solvent or in an organic solvent such as an aromatic carbide, an ether or a low molecular weight alcohol or a mixture of these solvents, at a temperature between 20 and 130 ° C, possibly under pressure.
• the dithioesters of general formula (III) can be obtained by the action of an organo-lithian derivative on a product of general formula: in which Het, X and Y are defined as above, followed by the action of carbon sulfide and then a product of general formula: wherein R 'is defined as above and Z represents a halogen atom, preferably a chlorine, bromine, or iodine atom or a reactive ester residue, preferably a mesyioxy or tosyloxy residue.
• the reaction is generally carried out in an anhydrous organic solvent such as hexamethylphosphorotriamide, generally added with an ether such as tetrahydrofuran, at a temperature between - 80 and - 40 ° C.
• anhydrous organic solvent such as hexamethylphosphorotriamide
• an ether such as tetrahydrofuran
• the organolitholith derivatives which are particularly suitable are preferably lithium alkyls such as butyllithium and isopropyllithium or phenyllithium, in solution in an inert solvent such as hexane, or lithium amides such as lithium diethylamide or lithium diisopropylamide.
• the heterocyclic derivatives of formula (IX) can be obtained by alkaline hydrolysis, preferably by means of an aqueous solution of an alkali hydroxide such as sodium hydroxide, of a salt of an isothiourea of general formula: at a temperature between 50 ° C and the boiling temperature of the reaction mixture, followed by the action of a product of general formula: in which Y is defined as above and the symbols Z ′, identical or different, each represent a halogen atom preferably a chlorine or bromine atom, or a reactive ester residue, preferably a mesyloxy or tosyloxy residue, at a temperature close to 20 ° C in the presence of an alkali hydroxide such as sodium hydroxide.
• an alkali hydroxide such as sodium hydroxide
• heterocyclic derivative of general formula from the alkaline hydrolysis of isothiourea of general formula (X), then reacting the product of general formula (XI) in the presence of an alkali hydroxide such as sodium hydroxide.
• the isothioureas of general formula (X), in the form of salts such as hydrochlorides, can be obtained by the action of thiourea on a heterocyclic derivative of general formula: in which Z "represents a halogen atom, preferably a chlorine or bromine atom, optionally in the form of a salt such as a halohydrate, operating in an organic solvent such as an alcohol (ethanol) with reflux temperature of the reaction mixture.
• Z represents a halogen atom, preferably a chlorine or bromine atom, optionally in the form of a salt such as a halohydrate, operating in an organic solvent such as an alcohol (ethanol) with reflux temperature of the reaction mixture.
• the heterocyclic derivatives of formula (XIII) can be prepared using, according to the heterocycle chosen, either the method of W. MATHES and H. SCHÜLY, Angew. Chem. Intern. Ed. 2, 144 (1963), i.e. the method of H. S. MOSHER and J. E. TESSIERI, J. Am. Chem. Soc. 73, 4925 (1957), also those of K. Y. NOVOTSKII et al., Khim. Getérotsikl. Soedin. (3), 412 (1970; C.A. 73, 25385z (1970) or A. HIRSCHBERG and P. E. SPOERRI, J. Org. Chem. 26, 2356 (1961).
• the products of general formula (XVI) can be prepared by the action of a magnesium derivative of general formula: in which R "and n are defined as above and Z '''represents a halogen atom such as a bromine or iodine atom, on an aldehyde of general formula (XV), operating by analogy with the method described by WB RENFROW, J. Org. Chem. 26, 935 (1961).
• the products of general formula (I) in which Het, X and Y are defined as above and R represents an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain can be obtained by the action of a organo-lithian derivative on a product of general formula (IV) followed by the action of an isothiocyanate of general formula: in which R "'represents an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain.
• the organolithium derivatives which are particularly suitable are preferably lithium alkyls such as butyllithium and isopropyllithium or phenyllithium, in solution in an inert solvent such as hexane, or amides such as lithium diethylamide or diisopropylamide lithium.
• the reaction is generally carried out in an anhydrous organic solvent such as hexamethylphosphorotriamide, generally added with an ether such as tetrahydrofuran, at a temperature between - 80 and - 40 ° C.
• anhydrous organic solvent such as hexamethylphosphorotriamide
• an ether such as tetrahydrofuran
• the new products according to the present invention can be purified by the usual physical methods, in particular crystallization and chromatography.
• the new products according to the invention have advantageous pharmacological properties associated with low toxicity.
• mice are particularly active as regulators of the cardiovascular system, in particular as antihypertensives. At doses between 0.1 and 100 mg orally, they lower blood pressure in spontaneously hypertensive rats (SHR rats) of the CKAMOTO-AOKI strain. The use of spontaneously hypertensive rats for the study of antihypertensive products is described by JL ROBA, Lab. Anim. Sci. 26, 305 (1976). Their lethal dose (DLg o ) in mice is generally greater than 300 mg / kg orally.
• the products of general formula (I) exhibit anti-ulcer and anti-secretory activity. This property can be demonstrated in rats, at doses of between 1 and 100 mg / kg orally, in particular in the technique of SHAY et al., Gastroenterology, 5, 43 (1945).
• the chromatographies were carried out with silica having a particle size of 0.063-0.20 mm or alumina having a particle size of 0.125-0.15 mm.
• Fractions 1 to 5 are combined and concentrated to dryness under reduced pressure (20 mm of mercury 2.7 kPa) at 50 ° C.
• the product thus obtained (8 g) is dissolved in 94 cm 3 of boiling ethanol; 0.4 g of bleaching black is added to the solution, filtered hot and then cooled for 15 hours to a temperature in the region of 5 ° C.
• the crystals which appear are separated by filtration, washed twice with 14 cm 3 in total of ethanol and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 20 ° C.
• the aqueous solution is extracted with 500 cm 3 of ethyl acetate.
• the organic phases are combined and washed 3 times with 4,500 cm 3 in total of distilled water then 2 times with 250 cm 3 in total of a 2N aqueous solution of hydrochloric acid.
• the product obtained (58 g) is chromatographed on 450 g of neutral silica gel contained in a column 5 cm in diameter; the column is then eluted with 1500 cm 3 of a cyclohexane-ethyl acetate mixture (95-5 by volume), with 4000 cm 3 of a cyclohexane-ethyl acetate mixture (90-10 by volume) , per 2000 cm 3 of a cyclohexane-ethyl acetate mixture (85-15 by volume), and per 2500 cm 3 of a cyclohexane-ethyl acetate mixture (80-20 by volume), collecting fractions of 500 cm 3 .
• Fractions 10 to 12 are combined and concentrated to dryness (20 mm of mercury; 2.7 kPa) at 50 ° C and the partially crystallized product obtained (10 g) is filtered, washed twice with 30 cm 3 in total of isopropyl ether and dried under reduced pressure (20 mm of mercury; 2.7 kPa) at a temperature in the region of 20 ° C; a first batch of 6 g of product is thus obtained.
• Fractions 13 to 20 are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 50 ° C.
• the second batch obtained (34 g) is combined with the first batch of 6 g and dissolved in 180 cm 3 of boiling isopropyl ether; 0.4 g of bleaching black is added to the solution, filtered hot and then cooled for 1 hour to 0 ° C.
• the crystals which appear are separated by filtration, washed twice with 52 cm 3 in total of isopropyl ether and dried under reduced pressure (1 mm of mercury; 0.13 kPa) at 35 ° C. 28.3 g of methyl (4-pyridyl) -2 tetrahydrotiophene-carbodithioate-2 are thus obtained, melting at 64 ° C.
• the organic extracts are combined, washed 3 times with 1500 cm 3 in total of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) at 70 ° C .
• the product obtained (33.3 g) is chromatographed on 33 g of neutral silica gel contained in a column 4.2 cm in diameter. Eluted successively with 4,000 cm 3 of a cyclohexane-ethyl acetate mixture (90-10 by volume) then with 7,000 cm 3 of a cyclohexane-ethyl acetate mixture (80-20 by volume), collecting fractions of 500 cm 3 .
• Chloromethylpyrazine can be prepared as described in the literature [A. HIRSCHBERT and P. Spoerri, J. Org. Chem., 26, 2356 (1961)].
• the organic extracts are combined, washed 3 times with 900 cm 3 in total of distilled water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 55 ° vs.
• the product obtained (12.4 g) is combined with 1 g of product prepared under the same conditions, and chromatographed on 154 g of neutral silica gel contained in a column 3.2 cm in diameter.
• the column is eluted with 500 cm 3 of a cyclohexane-ethyl acetate mixture (90-10 by volume), 1000 cm 3 of a cyclohexane-ethyl acetate mixture (80-20 by volume), 2250 cm 3 of a cyclohexane-ethyl acetate mixture (70-30 by volume) and 2500 cm 3 of a cyclohexane-ethyl acetate mixture (50-50 by volume), collecting fractions of 250 cm 3 .
• Fractions 19 to 25 are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 55 ° C.
• the product obtained (2.4 g) is dissolved in 50 cm 3 of boiling ethanol; 0.15 g of bleaching black is added to the solution and filtered hot, then cooled for 30 minutes to 0 ° C.
• the crystals which appear are separated by filtration, washed with 2 cm 3 of ethanol and then twice with 6 cm 3 in total of isopropyl ether and dried under reduced pressure (1 mm of mercury; 0.13 kPa) at 60 ° C. .
• 0.8 g of N-methyl (pyridazinyl-3) -2 tetrahydrothiophenecarbothioamide-2 is thus obtained, melting at 199 ° C.
• Isothiourea (3-pyridazinyl-methyl) -2 dihydrochloride can be prepared as described in the literature [NOVITSKII, K. YU. et al., Khim. Geterotsikl. Soedin., (3) 412 (1970); CA 73, 25385z (1970)].
• the product obtained (4.4 g) is chromatographed on 40 g of neutral silica gel contained in a column 2.6 cm in diameter. Eluted with 2000 cm 3 of a cyclohexane-ethyl acetate mixture (40-60 by volume) then with 800 cm 3 of ethyl acetate, collecting 200 cm 3 fractions. Fractions 4 to 14 are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 50 ° C. The product obtained (3.9 g) is dissolved in 45 cm 3 of boiling acetonitrile. The solution, added with 0.2 g of bleaching black, is filtered hot and then stored after cooling, for 1 hour at 0 ° C.
• the reaction mixture is stirred for 1 hour at a temperature in the region of - 65 ° C. and then a solution of 117 g of methyl isothiocyanate in 225 cm 3 of the mixture of hexamethylphosphorotriamide and tetrahydrofuran is poured in at 20 minutes at this temperature anhydrous (47-53 by volume).
• the mixture is then stirred for 30 minutes at -60 ° C. and then for 1 hour while allowing the temperature to gradually rise to 10 ° C. After adding 1 liter of distilled water, the mixture is extracted 6 times with 5 liters in total of ethyl acetate.
• the impurities are removed by eluting with approximately 50 liters of a mixture of cyclohexane and ethyl acetate, the ethyl acetate content of which gradually varies from 0 to 30%. Then eluted with pure ethyl acetate, collecting 3 fractions of 1 liter then 8 fractions of 0.7 liter. These last 8 fractions are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 60 ° C. The product obtained (20 g) is dissolved in a boiling mixture of 80 cm 3 of isopropyl ether and 40 cm 3 of ethanol.
• the organic extracts are combined, washed 5 times with 500 cm 3 in total of distilled water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7-- kPa) at 60 °. vs.
• the product obtained (20 g) is chromatographed on 30 g of neutral silica gel contained in a column 3.8 cm in diameter.
• Fractions 51, 52 and 53 are combined and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa) at 55 ° C.
• the product obtained (1.3 g) is dissolved in 17 cm 3 of boiling ethanol; 0.4 g of bleaching black is added to the solution, then filtered hot and stored, after cooling, for 3 hours at a temperature in the region of 5 ° C.
• the crystals which appear are separated by filtration, washed with 1 cm 3 of ethanol and twice with 2 cm 3 in total of isopropyl ether.
• 3-chloromethyl quinoline hydrochloride can be prepared according to the method described by J. KOTLER-BRAJTBURG, Acta Pol. Pharm. 25 (4), 383 (1968); CA 70, 87518 s.
• the present invention also relates to medicaments consisting of at least one product of general formula (I), in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, which may be inert or physiologically active.
• the medicaments according to the invention can be used orally, parenterally or rectally.
• compositions for oral administration tablets, pills, powders (especially in gelatin capsules or cachets) or granules can be used.
• the active product according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica.
• these compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or! Talc, a colorant, a coating (dragees) or a varnish.
• compositions for oral administration there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
• inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
• These compositions can also comprise substances other than diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers.
• the sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions.
• solvent or vehicle water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents.
• These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in a sterile injectable medium.
• compositions for rectal administration are suppositories or rectal capsules, which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
• the products of the invention are, according to the definition of the symbol Het given above, particularly useful in the treatment of gastrointestinal ulcers and, in the treatment of hypertension.
• the doses depend on the desired effect and on the duration of the treatment; they are generally between 25 and 1000 mg per day orally for an adult in one or more doses.
• the doctor will determine the dosage he considers most appropriate based on age, weight and all other factors specific to the subject to be treated.

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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